Autoimmune polyglandular syndrome type I (APS I), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare recessively inherited disease (MIM No. 240,300) that is more prevalent among certain isolated populations, such as Finnish, Sardinian and Iranian Jewish populations. The incidence of the disease among the Finns and the Iranian Jews is estimated to be 1:25000 and 1:9000, respectively, whereas only few cases in other parts of the world are found each year.
APECED is one of the two major autoimmune polyendocrinopathy syndromes. The causing factor of APECED has not yet been identified. The syndrome is characterized by lack of tolerance to numerous self-antigens and can therefore be considered as a prototype of organ-specific autoimmune diseases. In APECED, the patient develops chronic mucocutaneous candidiasis soon after birth, and later several organ-specific autoimmune diseases, mainly hypoparathyreoidism, Addison's disease, chronic atrophic gastritis with or without pernicious anemia, and in puberty gonadal dysfunction occur [Ahonen P, Clin. Genet. 27 (1985) 535–542]. An accepted criterion for diagnosis of APECED is the presence of at least two of the three main symptoms, Addison's disease, hypoparathyroidism and candidiasis, in patients [Neufeld, M. et al., Medicine 60 (1981) 355–362]. Immunologically, the major findings are the presence of high-titer serum autoantibodies against the effected organs, antibodies against Candida albicans, and low or lacking T-cell responses toward candidal antigens [Blizzard, R. M. and Kyle M., J. Clin. Invest. 42 (1963) 1653–1660; Arulanantham, K. et al., New Eng. J. Med. 300 (1979) 164–168; Krohn, K. et al., Lancet 339 (1992) 770–773; Uibo R. et al., J. Clin. Endocrinol. Metab. 78 (1994) 323–328]. The disease usually occurs in childhood, but new tissue specific symptoms may appear throughout life [Ahonen, P. et al., New Engl. J. Med. 322 (1990) 1829–1836]. APECED is not associated with a particular HLA haplotype, and both males and females are equally affected consistant with the autosomal recessive mode of inheritance.
The locus for the APECED gene has been mapped to chromosome 21q22.3 between gene markers D21S49 and D21S171 based on linkage analysis of Finnish families [Aaltonen, J. et al., Nature Genet. 8 (1994) 83–87]. Recently, Börses et al. reported a maximum LOD score of 10.23 with marker D21S1912 just proximal to the gene PFKL, and thus by linkage disequilibrium studies the critical region for APECED can be considered to be less than 500 kb between markers D21S1912 and D21S171. Locus heterogeneity was not revealed by linkage analysis of non-Finnish families [Björses, P. et al., Am. J. Hum. Genet. 59 (1996) 879–886].
For the APECED gene, the name “autoimmune regulator” or “AIRE” has been adopted by the scientific community after the priority date of the present application. Similarly the protein encoded by the AIRE gene is now called the “AIRE protein”.
Physical maps of human chromosome 21q22.3 have been developed using YACs, and bacterial based large insert cloning vectors [Chumakov et al., Nature 359 (1992) 380; Stone et al., Genome Res. 6 (1996) 218], and many laboratories have contributed to the construction of a transcription map of the whole chromosome and 21q22.3 in particular [Chen et al., Genome Res. 6 (1996) 747–760; Yaspo et al., Hum. Mol. Genet. 4 (1995) 1291–1304]. Numerous trapped exons from chromosome 21 specific cosmids and also physical contigs from the APECED critical region have been identified and partially characterized. In addition, a number of ESTs from the international human genome project have been mapped to the APECED critical region.
Recently, as part of the international efforts of generating the entire sequence of human chromosome 21 and international agreements on the immediate availability of this type of sequence data, the partial sequence of the APECED gene critical region was made available in GenBank by the Stanford Human Genome Center which is currently carrying out the sequencing of 1.0 Mb around the critical region of the APECED gene.
However, the precise location and the sequence of the APECED gene and the nature of the gene product have not so far been clarified. Thus at present the diagnosis of APECED is based mainly on developed clinical symptoms and typical clinical findings, e.g. the presence of autoantibodies against adrenal cortex or steroidogenic enzymes P450c17 and/or P450scc. The linkage analysis is seldom used. Further, means for natal or presymptomatic diagnosis of the disease are not easily available, since the linkage analysis provides only an indirect data through known gene markers and requires samples from several family members in several generations. Additionally, the linkage analysis is tedious and can be performed only in specialized laboratories by highly-skilled personnel.
Also the mapping of the carriers of the disease gene is presently based on the linkage analysis and thus not readily available.